19-50423008-G-T

Variant names:

• chr19-50423008-G-T
• rs11546996
• NM_003121.5:c.310G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003121.5(SPIB):​c.310G>T​(p.Ala104Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 151,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A104P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0000022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPIB NM_003121.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.797

Genes affected

SPIB (HGNC:11242): (Spi-B transcription factor) The protein encoded by this gene is a transcriptional activator that binds to the PU-box (5'-GAGGAA-3') and acts as a lymphoid-specific enhancer. Four transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

ENSG00000142539 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14486673).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPIB	NM_003121.5	c.310G>T	p.Ala104Ser	missense_variant	Exon 4 of 6	ENST00000595883.6	NP_003112.2
SPIB	NM_001243999.2	c.310G>T	p.Ala104Ser	missense_variant	Exon 4 of 6		NP_001230928.1
SPIB	NM_001244000.2	c.252G>T	p.Leu84Leu	synonymous_variant	Exon 4 of 6		NP_001230929.2
SPIB	NM_001243998.2	c.66+463G>T		intron_variant	Intron 3 of 4		NP_001230927.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPIB	ENST00000595883.6	c.310G>T	p.Ala104Ser	missense_variant	Exon 4 of 6	1	NM_003121.5	ENSP00000471921.1
ENSG00000142539	ENST00000599632.1	c.712G>T	p.Ala238Ser	missense_variant	Exon 8 of 10	5		ENSP00000473233.1

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151314 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000481

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000219 AC: 3 AN: 1372538 Hom.: 0 Cov.: 27 AF XY: 0.00000147 AC XY: 1 AN XY: 678318

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000282

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151314 Hom.: 0 Cov.: 27 AF XY: 0.0000135 AC XY: 1 AN XY: 73830

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000481

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	2.3
DANN	Benign	0.59
DEOGEN2	Benign	0.066	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.050	.;.;N
REVEL	Benign	0.028
Sift	Benign	0.44	.;.;T
Sift4G	Benign	0.48	T;T;T
Polyphen		0.020	B;.;B
Vest4		0.21
MutPred		0.19		Gain of glycosylation at A104 (P = 0.0108);Gain of glycosylation at A104 (P = 0.0108);Gain of glycosylation at A104 (P = 0.0108);
MVP		0.48
MPC		0.024
ClinPred		0.17	T
GERP RS		-2.1
Varity_R		0.049
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs11546996; hg19: chr19-50926265;